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Enric Carcereny



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    OA 17 - Immunotherapy II (ID 683)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      OA 17.02 - Updated Efficacy Results From the BIRCH Study: First-Line Atezolizumab Therapy in PD-L1–Selected Patients With Advanced NSCLC (ID 8006)

      14:30 - 16:15  |  Presenting Author(s): Enric Carcereny

      • Abstract
      • Presentation
      • Slides

      Background:
      The anti–PD-L1 mAb atezolizumab blocks the interactions between PD-L1 and its receptors, PD-1 and B7.1, thus restoring anti-tumor immunity. A Phase II study of atezolizumab monotherapy was conducted across multiple lines of therapy in PD-L1–selected patients with advanced NSCLC (BIRCH; NCT02031458). The primary analyses showed meaningful and durable clinical benefit with atezolizumab monotherapy in 1L and 2L+ NSCLC. Here we present updated survival data (median follow-up, 29.7 months) in patients receiving 1L atezolizumab.

      Method:
      Eligible patients had chemotherapy-naive, locally advanced or metastatic NSCLC without CNS metastases. Prior TKI therapy was required in patients with EGFR mutation or ALK rearrangement. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay). Patients who were TC2/3 or IC2/3 (PD-L1 expression on ≥ 5% of TC or IC) were enrolled. Atezolizumab 1200 mg was administered IV q3w until disease progression or unacceptable toxicity. The primary endpoint was independent review facility (IRF)–assessed ORR. Secondary endpoints included investigator (INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.

      Result:
      With a median follow-up of 29.7 months, median OS was 26.9 months (TC3 or IC3 subgroup) and 24.0 months (all treated patients); INV-assessed ORR was 35% (TC3 or IC3 subgroup) and 26% (all treated patients; Table). Among evaluable patients, the ORR was 31% for mutant EGFR (4/13) vs 23% for wild-type EGFR patients (24/103), and 31% for mutant KRAS (10/32) vs 24% for wild-type KRAS patients (16/66). No new safety signals were observed.

      Conclusion:
      With more than 2 years of follow-up, atezolizumab continued to demonstrate durable clinical activity in 1L NSCLC, regardless of EGFR and KRAS mutational status. These data suggest that atezolizumab monotherapy has promising activity as a frontline therapy. Ongoing Phase III trials are evaluating atezolizumab-based regimens vs chemotherapy in 1L NSCLC.

      Endpoint (95% CI) TC3 or IC3[a ](n = 65) TC2 or IC2[b] (n = 73) All Treated Patients (N = 138)
      INV-assessed ORR, % 35% (23.9, 48.2) 18% (9.8, 28.5) 26% (19.0, 34.2)
      EGFR mutant/wild-type, % 25%/33% 33%/15% 31%/23%
      KRAS mutant/wild-type, % 38%/33% 25%/15% 31%/24%
      mDOR, mo 16.5 (8.5, NE) 12.5 (8.3, 17.9) 13.1 (9.9, NE)
      mOS, mo 26.9 (12.0. NE) 23.5 (18.1, NE) 24.0 (18.1, 31.9)
      12-mo OS rate, % 61% (49.0, 74.0) 71% (59.8, 81.5) 66% (58.1, 74.6)
      24-mo OS rate, % 52% (39.3, 65.2) 49% (37.0, 61.1) 50% (41.5, 59.2)
      30-mo OS rate, % 48% (35.3, 61.5) 39% (27.2, 51.2) 43% (34.3, 52.1)
      mPFS, mo 7.3 (4.9, 12.0) 7.6 (4.0, 9.7) 7.6 (5.7, 9.7)
      12-mo PFS rate, % 38% (25.1, 49.9) 30% (19.2, 41.2) 34% (25.3, 41.9)
      24-mo PFS rate, % 28% (16.5, 40.0) 13% (4.5, 21.5) 20% (12.9, 27.5)
      30-mo PFS rate, % 19% (5.4, 33.5) 9% (1.4, 16.4) 14% (6.5, 21.9)
      NE, not estimable. [a ]TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells.[b ]TC2/3 or IC2/3 excluding TC3 or IC3.


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    P1.05 - Early Stage NSCLC (ID 691)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
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      P1.05-015 - Major Pathological Response as a Predictive Value of Survival in Early-Stage NSCLC  After Chemotherapy: Cohort of NATCH Phase III Trial (ID 9893)

      09:30 - 16:00  |  Presenting Author(s): Enric Carcereny

      • Abstract

      Background:
      In early-stage non-small cell lung cancer (NSCLC) patients, randomized phase III NATCH trial reported no statistically differences in disease-free survival (DFS) or overall survival (OS) with the addition of preoperative or adjuvant chemotherapy to surgery. In pre-operative arm, those patients who achieved a complete response obtained a benefit in 5-year DFS rate (59% vs. 38%). Recently, major pathological response (MPR) to preoperative therapy (10% or less of residual viable tumor after preoperative chemotherapy) has reported as surrogate marker of OS. We assess to validate this prognostic factor in a cohort of patients included the NATCH trial.

      Method:
      Retrospectively MPR was collected in a cohort of 57 early-stage NSCLC patients treated in the preoperative arm into NATCH trial from 2 institutions. OS according to MPR was analysed (long-rank test) in the whole population and by histologic subtype

      Result:
      In this cohort, median age was 67 years (47-78), 48 (84%) were males, 26 (46%) squamous subtype. By stage according to 6[th] TNM: 9 (16%) stage IA, 35 (61%) stage IB, 12 (21%) stage IIB and 1 (2%) stage IIIA. All except 3 completed 3 cycles of preoperative treatment. Surgical procedures: 81% lobectomies or bi-lobectomies, 14% pneumonectomies, 5% no surgery. In the whole population, there was a trend toward 5-year OS benefit among those patients with MPR (84.6% vs. 58.5%, p=0.106). According to histologic subtype, squamous tumours with MPR had significantly better 5-year OS (100% vs. 47.1%, p=0.026), but not in adenocarcinoma subtype (66.7% vs. 66.7%, p=0.586).

      Conclusion:
      MPR is a prognostic value in squamous NSCLC patients who receive preoperative chemotherapy. Validation in extended cohort merits further evaluation.

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-073 - TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC (ID 8956)

      09:30 - 16:00  |  Author(s): Enric Carcereny

      • Abstract
      • Slides

      Background:
      Overexpression of several receptor tyrosine kinases (RTKs) substitutes EGFR signaling in EGFR-mutant NSCLC. The MET ligand hepatocyte growth factor (HGF) provides an alternative signaling mechanism for EGFR by inducing inter-receptor cross talk with EphA2, CUB domain-containing protein-1 (CDCP1) or AXL. SHP2, a non-receptor protein tyrosine phosphatase is central in signal transduction downstream of RTK signaling and in Src activation. We previously demonstrated that STAT3 and Src-YAP1 signaling limits EGFR TKI efficacy in EGFR-mutant NSCLC. We are now exploring the possibility of multiple RTK activation through a Src-YAP1-mediated transcriptional program. We are evaluating whether combined EGFR inhibition with TPX-0005, a novel orally available multikinase inhibitor and potent Src/FAK and JAK2 inhibitor, can be more efficient than EGFR inhibition alone in EGFR-mutant NSCLC cells.

      Method:
      We studied the mRNA expression levels of stromal HGF and tumor RTKs, AXL, CDCP1, MET, and EphA2, as well as SHP2, and clinical outcome in baseline samples of 64 EGFR-mutant NSCLC patients treated with first-line EGFR TKI. We combined in vitro approaches to explore whether gefitinib or osimertinib combined with TPX-0005 can abolish STAT3 and Src-YAP1 and downregulate the expression of RTKs.

      Result:
      High levels of AXL, CDCP1 and SHP2 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 14.5 and 23.4 months for patients with high and low AXL mRNA, respectively (p=0.0359). Median PFS was 9.1 and 20.2 months for patients with high and low CDCP1 mRNA, respectively (p=0.0179). Tumoral EPHA2 and MET or stromal HGF levels did not affect PFS. Median PFS was 11.4 and 24.1 months for patients with high and low SHP2 mRNA, respectively (p=0.0094). The combination of gefitinib/osimertinib with TPX-0005 resulted in highly synergistic suppression of cell viability and reduced colony formation in two EGFR-mutant cell lines. The combination abolished the EGFR inhibition-induced STAT3 and YAP1 phosphorylation, as confirmed by western blotting and immunofluorescence. The results of TaqMan quantitative-PCR assay revealed that gefitinib/osimertinib plus TPX-0005 reduced the mRNA levels of AXL, CDCP1 and MET, an effect that could not be obtained with EGFR inhibition alone. In vivo experiments are ongoing.

      Conclusion:
      AXL and CDCP1 are adverse predictive markers of PFS in EGFR-mutant NSCLC patients. STAT3 and Src-YAP1 signaling limits the efficacy EGFR TKI. Combined EGFR inhibition with TPX-0005 (currently in phase I clinical testing) is a particularly attractive strategy

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